Amyotrophic Lateral Sclerosis (ALS) is a mortal neuromuscular disease that affects 2800 persons in Spain, with two new cases being diagnosed each day. Abnormal aggregates of the protein “TDP-43” (transactive response DNA binding protein 43 kDa) are found in >95% of dying motor neurons, and have been linked to other neurodegenerative disease, including Alzheimer’s disease and Frontotemporal Lobar Degeneration. Aggregation of TDP-43 was traced to a small, Asn- and Gln-rich region of the protein spanning residues 341-357, but the conformation of this segment and how it oligomerizes into harmful aggregates was unknown. Here, on the basis of multiple biochemical assays and biophysical experiments, IQFR investigators in collaboration with scientists from Columbia University (New York), the Cajal Institute (CSIC), IMDEA Nanoscience (CAM), and the International Centre for Genetic Engineering and Biotechnology (Trieste, IT) show that this segment’s beta hairpin motifs assemble into an amyloid-like structure with an unusual fibril morphology. Using computational methods, they have advanced an amyloid-like structural model for the aggregate in which TDP-43 (341-357) beta hairpins dock in a novel, parallel topology. This structural model will likely aid our understanding of TDP-43’s role in neurodegenerative diseases and may help guide the search for treatments.

M. Mompeán, R. Hervás, Y. Xu, T.H. Tran, C. Guarnaccia, E. Buratti, F. Baralle, L. Tong, M. Carrión-Vázquez, A.E. McDermott, D.V. Laurents 
J. Phys. Chem. Letters, June 2015, doi: 10.1021/acs.jpclett.5b00918